This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging, the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging, as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices, immunohistochemistry with a battery of stains, separate microarray analysis of individual rat brains, EEG monitoring of sleep patterns, and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly, behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral, electrophysiological, sleep monitoring, microarray and immunohistochemical analyses, to test the proposition that conversion these interventions may reduce/reverse UBA symptoms, and, if so, to determine through which brain pathways this occurred. Overall, these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers, and should importantly determine the role of age in modulating stress impact. Further, the proposed intervention studies should have direct translational relevance. PUBLIC HEALTH RELEVANCE: This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function in an established rat model of aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy brain aging, focusing on changes beginning around midlife and will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects of psychosocial stress. Therefore, the proposed studies should have both predictive and therapeutic value in determining the course of human brain aging.